Abstract
BackgroundCurrent management strategies for rheumatoid arthritis (RA) aim to minimise joint inflammation using disease modifying anti-rheumatic drugs (DMARDs), including biologics. Remission, an achievable goal in some patients; however, many patients still fail to achieve low disease activity or remission despite receiving DMARDs. Disease activity is assessed using composite tools such as the disease activity score (DAS) which incorporate both objective and subjective measures. Some measures are influenced by additional factors like pain and may not accurately reflect the inflammatory burden. This makes monitoring disease activity in clinical practice challenging. Patients with high disease activity are likely to have their DMARD therapy increased. However, patients with moderately active disease often have insufficient treatment changes. Guidance on how to treat patients with moderate disease activity is lacking. There is also no international consensus on what is considered an adequate treatment response for these patients. The over-arching aim of this thesis was to evaluate the impact of moderately active RA using existing clinical evidence and to use this information to determine whether there was a reasonable case for treating patients with moderately active disease more intensively.
Methods
The research involved five inter-related studies.
The first study identified changing patterns of disease activity and disability over time based on an analysis of patients seen in routine treatment settings over the previous 20 years. The second study systematically reviewed current RA guidelines and considered what advice they provided about treating moderately active RA. The third study explored how reductions in disability and improvements in quality of life were affected by alternative assessments of reductions in disease activity in two trials of intensive treatment strategies in active RA. The fourth study evaluated RA patients at risk of persistent active disease during conventional treatment. It sought to design a simple algorithm to identify patients with persistent active disease despite DMARDs. It also considered whether patients at higher risk of persistent disease activity would benefit from intensive treatment.
The final study used ultrasound assessments to determine if RA patients with similar clinical disease activity assessed by DAS who also had clinical features of fibromyalgia had lower levels of joint inflammation than similar patients without fibromyalgia.
Results The five studies provided different types of evidence about the prevalence and impact of persistent moderately active RA. Taken together they make a strong case that some patients with moderately active RA merit more intensive treatment.
Firstly, sequential studies of 1324 RA patients showed that from 1996 to 2014 there were temporal increases in the use of DMARDs. During this time disease activity scores fell and remissions increased. In contrast disability scores were unchanged. Secondly, the systematic review of 22 RA guidelines showed 20 recommended targeting remission and 16 suggested low disease activity as an alternative. All guidelines recommend treating active RA but only 13 made recommendations specifically for moderate disease. Thirdly, in trials in both early and established RA, the magnitude of change in disability, the HAQ and EQ5D, was greater in both settings in ‘good responders’ where the end DAS28 is in low disease activity or remission, compared with ‘moderate responders’ where some disease activity persists. Patients who achieve a good response should continue on treatment. However, continuing such treatment strategies is more challenging when only a moderate response is achieved. Forthly an anlysis of an observational cohort using regression modelling identified three main predictors of persisting active disease; tender joint counts, disability scores and the erythrocyte sedimentation rate. Using these predictors in a four-point prediction score predicted persisting active disease in early and established RA. Patients with high scores were more likely to have persistently active disease at 6 and 12 months.
Finally, an observational study of 47 patients with active RA on DMARDS found those patients meeting criteria for fibromyalgia also had higher scores for disease activity, depression, disability and fatigue. Those meeting both the joint count and classification fibromyalgia criteria had significantly lower levels of grey scale and power Doppler synovitis on ultrasound.
Conclusion
The research presented here demonstrates that RA outcomes have improved over time. Despite significant advances in treatment paradigms and the wider availability of novel targeted drug therapies, many patients fail to achieve remission or low disease activity and continue to suffer disability. There remains a sizeable proportion of patients with moderately active disease. These patients also have poor outcomes. The disaease activity and disability measures are also affected by non-inflammatory factors and how these are addressed needs to be better understood. This may be time to revisit existing strategies and the composite tools used in clinical practice if we are to continue to improve outcomes for more patients with RA.
| Date of Award | 1 Jul 2023 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | David Scott (Supervisor) & James Galloway (Supervisor) |